Summary Cerebrovascular reactivity (CVR) is clinical measure of cerebrovascular function influenced by micro- and macrovascular effects including delay in blood arrival time, delay in tissue reponse, and chronic vasodilation. Individually and simultaneously determing blood flow delay, CVR magnitude and CVR delay using time delay analysis methods we have developed will yield much richer and more specific information about underlying vascular pathology than is currently available. In healthy tissue, vasodilation adjusts vessels' resistance to flow, and modulates cerebral perfusion in response to changing demands for oxygen and nutrients; this ability is reduced or absent in many forms of cerebrovascular pathology. Cerebrovascular reactivity (CVR), and the related quantity cerebrovascular reserve, are measures of brain blood vessels' capacity for vasodilation, which may offer useful clinical information in patients at risk for cerebral ischemia associated with chronic stenosis or occlusion of cerebral blood vessels. Traditional methods of CVR analysis, which correlate a modified schedule of CO2 changes in inhaled gases voxelwise with BOLD fMRI signal, lead to systematic underestimation of CVR magnitude in regions where the response is delayed with respect to the gas administration schedule. We have validated a method to detect and quantify local delays in blood flow arrival, and to derive corrected CVR magnitude maps. Even after the true magnitude of the CVR is known, questions remain regarding whether the delay in CVR is due to delayed arrival of blood in the tissue of interest (upstream pathology), or delayed vasodilation in impaired tissue (local pathology), or a combination of both. Therefore, we propose to use both vasodilatory and nonvasodilatory gas manipulations in combination with near-infrared spectroscopy during fMRI imaging to evaluate each source of delay separately. This proposal capitalizes on the technical resources available at McLean Hospital / Harvard and the unique clinical resources available at the Vanderbilt University Medical Center to develop, implement, and evaluate a clinical protocol for the noninvasive assessment of not only true CVR magnitude, but also the individual contributors to CVR and blood circulation times as they relate to underlying circulatory physiology. We will first study 70 healthy control subjects between 20 and 70 years old with the calibrated CVR method to separately determine CVR magnitude and delay time (Aim 1), and separately evaluate two components of CVR delay: blood arrival time, and tissue reactivity time (Aim 2). We will then perform the same measures in a population of 30 patients with intracranial atherosclerotic stenosis, and 15 age-matched controls, to test the hypothesis that blood arrival time delay is increased and CVR magnitude is decreased in areas affected by stenosis (Aim 3). Previous work strongly suggests that the relative contribution of these two factors will help differentiate different types of pathology with different etiologies.